Voluntary Wheel Running Regulates Tumor Immunogenicity and Response to Immune Checkpoint Therapy

Abstract

Exercise training is associated with reduced tumor growth and enhanced intratumoral immune cell infiltration. As tumor immunogenicity is vital for the clinical response to immunotherapeutic agents, we aimed to investigate the role of exercise in promoting the response to immune checkpoint inhibition. We observed that voluntary wheel running in B16 tumor-bearing mice increased immune checkpoint expression (PD-L1, PD-L2, B7.1 and B7.2), and this induced expression was associated with the tumor stroma, i.e. fibroblasts and dendritic cells. PD-L1 expression depended on IFN-γ stimulation from infiltrating cytotoxic immune cells, whereas B7.1 expression depended exercise-mediated mobilization of dendritic cells, and was augmented by aspirin treatment. Combining voluntary wheel running with anti-PD-L1 treatment markedly (-83%, p<0.05) reduced B16 tumor growth and augmented immune checkpoint expression and intratumoral immune cell infiltration. This study demonstrates that exercise can make tumors more prone to respond to immune therapy, highlighting that exercise may enhance anti-cancer treatment efficacy.